The aim of this study is to investigate relations among molecular genetic, brain, and psychophysiological systems underlying limbic brain structure and function in young adult males and females with the fragile X premutation. The fragile X premutation, associated with a CGG repeat expansion of 55 to 200 in the FMR1 gene on the X chromosome, is a relatively common genetic condition, present in one per 813 men and one per 250 women. Until recently, it was believed that carriers of the premutation were clinically unaffected. Recent evidence, however, shows that a proportion of these individuals have significant social, emotional, and cognitive deficits, social anxiety, even autism and mental retardation. The investigators have found that some will go on to develop in their later years a newly discovered, progressive neurological disorder, fragile X associated tremor ataxia syndrome (FXTAS). They have evidence that FXTAS is related to a toxic gain-of-function effect from elevated FMR1-mRNA in the premutation range. They hypothesize that limbic dysfunction underlies social-emotional and memory deficits in young adult individuals with the premutation. In the current study, they will use structural and functional MRI to determine whether men and women with the premutation (ages 18 to 45 years), in comparison to matched sibling control groups, demonstrate abnormal brain morphology and function in limbic brain regions, focusing on the hippocampus and amygdala. They will also examine psychiatric symptoms related to mood disorder and psychophysiological indices of anxiety in these subjects, and examine whether measures of FMR1 gene function, including elevated mRNA, are associated with the morphology and function of limbic brain regions. Hopefully, the proposed research will lead to a better understanding of gene-brain-behavior relations associated with the FMR1 premutation. In addition, the knowledge of multiple systems of involvement in the premutation generated from this work will lay the groundwork for more targeted psychopharmacological, behavioral, and perhaps genetic intervention studies in the future. The investigation of a relatively homogeneous single gene condition such as the fragile X premutation provides a model system for understanding links among molecular genetic, brain, and psychiatric features of more complex disorders. [unreadable] [unreadable]